A recent study demonstrated that the combination of lenalidomide and obinutuzumab is highly active with durable remissions in relapsed follicular lymphoma (J Clin Oncol 2017; doi:10.1200/JCO.2017.35.15_suppl.7531).
Treatment of relapsed follicular lymphoma remains a significant challenge, and salvage therapies are often associated with toxicity and limited control. Oftentimes, patients can develop resistance to chemotherapy and a majority will relapse following a standard therapy regimen.
Given the challenges associated with relapsed follicular lymphoma, study authors hypothesized that the “immunologic properties of obinutuzumab and lenalidomide would be synergistic.” The main objective of the trial was to determine the safety and efficacy of lenalidomide with obinutuzumab in relapsed follicular lymphoma.
Studies has proven that lenalidomide, an immunomodulatory agent, and rituximab are highly active among follicular lymphoma patients. In a phase II study of this combination among indolent non-Hodgkin lymphoma, including follicular lymphoma, the treatment was well-tolerated with a high response (Lancet Oncol 2014;15(12):1311-1318).
According to the data, complete responses occurred in 65 patients (63%, 95% CI 53-72) and partial responses in 28 (27%, 19-37). Of the 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. An international phase III study (NCT01476787) is currently underway to compare this treatment regimen with chemotherapy in untreated follicular lymphoma patients.
Preclinical studies have shown that combining lenalidomide with anti-CD20 molecules results in a synergistic antitumor effect (Am J Hematol 2009;84(9):553-559). Obinutuzumab, which was approved for relapsed follicular lymphoma in 2016, has increased antibody-dependent cellular cytotoxicity compared to rituximab, according to preclinical models.
The approval of obinutuzumab is based on GADOLIN, a phase III open-label, multicenter, randomized two-arm study. The results showed that, in people with follicular lymphoma whose disease progressed during or within 6 months of prior rituximab-based therapy, obinutuzumab plus bendamustine followed by obinutuzumab alone demonstrated a 52 percent reduction (HR=0.48, 95 percent CI 0.34-0.68, p<0.0001) in the risk of disease worsening or death, compared to bendamustine alone, as assessed by an independent review committee.
GADOLIN (NCT01059630) included 413 patients with indolent non-Hodgkin lymphoma, including 321 patients with follicular lymphoma, whose disease progressed during or within 6 months of prior therapy. This study also evaluated the safety of obinutuzumab. The most common grade 3-4 side effects of this regimen were low white blood cell counts, infusion reactions, and low platelet counts.
Building on this body of previous research, Fowler et al. sought to take this knowledge one step further and evaluate the combination of lenalidomide and obinutuzumab among patients with relapsed follicular lymphoma.
Patients with grade 1-3a follicular lymphoma who had progressed following at least one treatment were enrolled in the open label phase I/II study (NCT01995669). Eligible participants showed no evidence of transformation and had no active infection of malignancy.
Among the enrolled follicular lymphoma patients (n=36), 28 (78%) had grade I/II disease and eight (22%) were grade IIIa. Seventeen patients were male and 19 were female; the median age was 62 (range 35-82). Nineteen percent of patients had bone marrow involvement. Additionally, the median number of prior therapies was two and among the enrolled patients, nine (25%) were rituximab refractory.
Lenalidomide (10mg, 15mg, 20mg) was administered on days 2-22 of a 28-day cycle with a fixed dose of obinutuzumab (1,000 mg) on days 1, 8, 15, and 22 of cycle 1 and on day 1 for up to 12 cycles (28 days/cycle). Obinutuzumab was then given every 2 months for up to 30 months in patients who responded following doublet therapy.
Researchers planned three cohorts with 10 mg, 15 mg, and 20 mg of lenalidomide during dose escalation. Phase II of the study enrolled 30 patients at a recommended dose with efficacy and safety as primary endpoints.
All 36 patients with follicular lymphoma enrolled (six in dose escalation and 30 at MTD) were eligible for efficacy and safety analysis.
No dose-limiting toxicities were observed in phase I, according to researchers, and 20 mg of lenalidomide was used for phase II.
Investigators reported an overall response rate of 100 percent with 78 percent (95% CI 60.85-89.88%) of patients reaching a complete response. The median time to response was 3 months. Additionally, all patients who were rituximab refractory responded. At a median follow up of 14 months, 10 patients had progressed. According to researchers, the estimated 24-month progression-free survival was 61 percent (95% CI 43-87%).
Data supports 20 mg as the recommended phase II dose of lenalidomide in combination with obinutuzumab. To date, 72 percent of patients (26/36) remain in treatment on extended dosing with obinutuzumab.
The data confirms the safety of this combination with toxicities similar to prior studies, according to researchers.
The most common all-grade, non-hematologic toxicities included fatigue (83%), diarrhea (67%), and rash (53%). Toxicities grade 3 or higher included neutropenia (23%), infection (11%) and fatigue (8%). Hematologic adverse events included anemia, neutropenia, and thrombocytopenia. Neutropenia (grade 3 or higher) occurred in 25 percent of patients (9/36).
Rash was most common during the first cycle and the majority of cases were grade 1 or 2, noted study authors. Significant tumor lysis was not observed. One secondary, non-hematologic cancer occurred and no deaths were observed in the study.
“Lenalidomide and obinutuzumab [treatment] is highly active with durable remissions in relapsed follicular lymphoma, with all patients responding and 78 percent achieving complete response,” study authors concluded. “The majority of patients remain on therapy and the combination appeared safe.”
Frontline studies of the combination are currently enrolling patients and correlatives are ongoing to identify biomarkers of response, according to researchers.
There are quite a few choices when it comes to salvage therapies for patients with relapsed disease, such as PI3K inhibitors, which look extremely promising as do others, noted Pamela Crilley, DO, Chair, Department of Medical Oncology at Cancer Treatment Centers of America.
“This [study] is another example of an effective salvage regimen for patients with relapsed indolent lymphoma,” she commented. “This trial has a very high response rate as well as fairly durable response. Additionally, important to note is the toxicity appears low and manageable.
“One of the issues with follicular lymphoma is that when you try to get a patient into remission you try to have it last as long as possible because this disease is characterized by recurrent disease,” she continued. “We do have several options for salvage treatments in this arena, but we are always looking for what will give us a long duration of response with a good safety profile for the patient. Therefore, these two drugs are very impressive in terms of efficacy and the researchers have chosen a dose of lenalidomide that is well-tolerated.”
The complete remission rate among patients in the study who received lenalidomide plus obinutuzumab was quite high, Crilley, who is also a hematologist/oncologist and medical oncologist at Eastern Regional Medical Center in Philadelphia, remarked. “Given the positive short-term results of the study I believe this could be a viable treatment option to add to the arsenal of therapies available to follicular lymphoma patients with relapsed disease.”
While the data shows significant promise for patients with relapsed follicular lymphoma, Crilley noted the importance of long-term follow-up to track the duration of response as well as the need for an analysis with more patients. “Next steps will include an analysis of this combination in a larger, phase III trial to see where it will fit compared to other salvage regimens,” she reiterated. “This is a very intriguing study and I look forward to seeing the long term follow-up.”
To date, there hasn't been a standard treatment option for patients who have relapsed/refractory follicular lymphoma,” Crilley noted. “There are a number available treatments both in the U.S. and Europe and oftentimes the patients will receive different salvage regimens.
“The key to any regimen is to provide as long and as high-quality a remission as possible with minimum side-effects,” she continued. “Additionally, we are in an era where the goal is to utilize more oral agents or a combination with effective drugs, such as lenalidomide. Given these patients are essentially living with a chronic disease that may require intermittent treatment the side-effect profile in both the short- and long-term is extremely important to quality of life.”
Looking to the future, Crilley noted that there are several significant studies underway that will provide more answers as well as therapy options for this often difficult-to-treat patient population.
Catlin Nalley is associate editor.